β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells
β-Catenin mediates tumor-induced immunosuppression by inhibiting cross-priming of CD8+ T cells
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DOI：
10.1189/jlb.0613330
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发表时间：
2014-01-01
影响因子：
5.5
通讯作者：
Jiang, Aimin
中科院分区：
文献类型：
--
作者：
Liang, Xinjun;Fu, Chunmei;Jiang, Aimin
肿瘤激活DC中的β-连环蛋白，通过抑制交叉引发来抑制CD8免疫； β-连环蛋白抑制的 CD8 免疫可以通过增强交叉引发来挽救。尽管CD8+T细胞对于抗肿瘤免疫至关重要，但肿瘤常常通过免疫抑制来逃避CD8+T细胞的监视。作为抗原特异性免疫反应的启动者，DC可能在调节免疫与肿瘤抗原耐受之间的平衡中发挥核心作用，并且专门具有在MHC I类分子上交叉呈递外源肿瘤抗原以启动CD8(+) T细胞免疫的能力。然而，目前尚不清楚肿瘤是否以及如何调节 DC 功能来抑制 CD8(+) T 细胞反应。我们之前已经表明，DC 中的β-catenin 信号传导可促进DC 介导的CD4(+) T 细胞耐受。在这里，我们测试了这样的假设：DC中的β-连环蛋白通过抑制DC交叉启动的能力来介导肿瘤诱导的CD8+T细胞免疫抑制。 -连环蛋白在 DC 中被体内和体外多种肿瘤激活。患有黑色素瘤的 B16 小鼠在接种与肿瘤抗原融合的 DC 靶向抗 DEC-205 mAb 疫苗后，表现出 CD8(+) 免疫力减弱，与 DC-连环蛋白（活性）小鼠相似。来自DC-连环蛋白（活性）和荷瘤小鼠的DC缺乏交叉启动，并且在这些小鼠中启动的抗原特异性CD8（+）T细胞导致CD8（+）记忆反应减弱。重要的是，DC-连环蛋白(-/-)小鼠完全消除了肿瘤介导的交叉引发抑制，表明肿瘤诱导的交叉引发抑制依赖于-连环蛋白。最后，在启动或回忆阶段增强交叉启动可以挽救DC-连环蛋白（活性）和荷瘤小鼠中-连环蛋白抑制的CD8（+）免疫力。因此，α-连环蛋白介导的交叉引发抑制代表了肿瘤用来实现免疫抑制的一种新的、潜在的通用机制。
Tumors activate -catenin in DCs to suppress CD8 immunity by inhibiting cross-priming; -catenin-suppressed CD8 immunity could be rescued by enhancing cross-priming. Whereas CD8(+) T cells are essential for anti-tumor immunity, tumors often evade CD8(+) T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8(+) T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8(+) T cell responses. We have shown previously that -catenin signaling in DCs promotes DC-mediated CD4(+) T cell tolerance. Here, we tested the hypothesis that -catenin in DCs mediates tumor-induced suppression of CD8(+) T cell immunity by inhibiting the ability of DCs in cross-priming. -Catenin was activated in DCs by multiple tumors in vivo and in vitro. B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8(+) immunity, similar to DC--catenin(active) mice. DCs from DC--catenin(active) and tumor-bearing mice were deficient in cross-priming, and antigen-specific CD8(+) T cells primed in these mice resulted in dampened CD8(+) memory responses. Importantly, DC--catenin(-/-) mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on -catenin. Finally, enhancing cross-priming at the priming or recall phase rescued -catenin-suppressed CD8(+) immunity in DC--catenin(active) and tumor-bearing mice. Thus, -catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.